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postherpetic neuralgia treatment and painful diabetic neuropathy
Introduction
Although the exact prevalence of neuropathic pain is not known exactly, it is estimated that this symptom is presented by approximately 1% of the population.The causes are multiple, including trauma, infections, metabolic disorders, chemotherapy, surgery, radiotherapy, the effect of neurotoxins, nerve compression, inflammation or tumor infiltration.It can be classified as central or peripheral, depending on the location of the lesion.Hyperalgesia and allodynia are characteristics of neuropathic pain that are usually associated with parstetesia or burning sensation.
The most frequent causes of neuropathic pain are postherpetic neuralgia (NPH) and painful diabetic neuropathy (NDD).The first is a herpes zoster complication defined as the pain that persists for more than three months after the disappearance of skin lesions.It occurs between 10% and 34% of people suffering from this condition, although in those over 60 years the incidence is approximately 50%.
The NDD, in turn, is one of the most frequent complications of diabetes and, in the western world, is the most common cause of neuropathy.It is usually presented as a distal, symmetric, painful sensitive polyneuropathy, which alters the performance and quality of life of patients.It is estimated that between 10% and 66% of individuals with diabetes have neuropathy and between 10% and 20%, NDD, although the frequency reaches 32% of patients with type 2 diabetes.
At present, treatments available for neuropathic pictures are useful only to reduce symptoms, especially pain.
This article analyzed the effectiveness of the drugs available for the treatment of NPH and NDD.
Methods
The authors analyzed the information from randomized and placebo controlled studies carried out in patients over 18 years of age with NPH and NDD, available in web databases of Science, Pubmed and Medline.These articles evaluate the efficacy and limitations of drugs and available drug combinations.
For the analysis, the researchers defined the effectiveness of a drug such as pain reduction of at least 50%, but since this information could not be extracted from all studies, the authors also included patients who presented a decreaseSignificant of the symptom after a certain treatment.
They selected 76 studies that met the criteria established for the review: to be randomized and double blind, and describe the rate of abandonment of treatment.Of these works, 26 included patients with NPH, 49 included subjects with NDD and one involved patients with both forms of neuralgia.
Pharmacological treatment of neuropathic pain
Antidepressants
Tricyclic antidepressants (ADT) were for years the first choice drugs for neuropathic pain treatment.These inhibit serotonin and norepinephrine reuptake in the central nervous system (CNS) and, thus, activate the descending paths of analgesia;In addition, they inhibit nerve hyperexcitability.
In randomized studies, placebo controlled, double blind and comparative, it has been observed that amitriptyline and desipramine are effective for the treatment of NPH.67% of patients treated with amitriptyline and 63% ofThose who received Desipramina referred to a pain relief at least moderate.Amitriphylin was superior to Lorazepam and maprotylin, but demonstrated efficacy similar to nortriptyin in patients with NPH.However, the incidence of adverse effects (EA) was greater with amitriptyline than with nortriptyin.In another study it was demonstrated that the combination of amitriptyline with fluphenazine was superior to ADT alone.
In three studies the effectiveness of ADT was evaluated in patients with NDD.Between 51% and 58% of patients referred to pain relief with these drugs.Amitriptyline was slightly higher than maprotylin, and clomipramine in doses of 50 to 75 mg/day was superior to desipramine in doses of 50 to 200 mg/day.The desipramine response rate was 36% and clomipramine, 52%.The combination of flugenazine with nortpthylin was more effective in this population.
The authors warn that most of the studies in which the effectiveness of ADT was analyzed were transverse design and included few patients.
The most frequently described EA of ADT are dizziness, xerostomy, sedation and blurred vision.In patients with heart disease, it can cause arrhythmias, increase the incidence of acute myocardial infarction and congestive heart failure, and in the elderly, increase the risk of falls due to orthostatic hypotension.Therefore, added to the pharmacological interactions of these drugs, their use in practice is limited.In addition, these drugs should be used with caution in patients with high risk of suicide, glaucoma and urinary retention.
Serotonin and norepinephine reuptake inhibitors (IRSN), such as venlafaxin and duloxetine, are also effective for neuropathic pain treatment.It has been shown that prolonged release venlafaxin in doses of 75 to 225 mg/day significantly reduces pain by NDD, although in another study it was observed that it would not be superior to imipramine.The authors point out that the low efficacy of venlafaxin recorded in that study could be due to the design and the population included in that clinical trial.The most frequent EA of venlafaxin are dyspepsia, nausea, sweating, drowsiness and insomnia.
In a study in which 457 patients with NDD were included the efficacy of the duloxetine, drug that in doses of 60 to 120 mg/day caused a significant decrease in pain and performance improvement.These results were confirmed in two other clinical trials.The most frequent EA of duloxetine are drowsiness, nausea, dyspepsia, hyperhidrosis, constipation, dizziness and xerostomy, which in the studies were listed as mild to moderate.
The results of the trials in which the effectiveness of selective serotonin reuptake (SSRI) in patients with NDDs are contradictory was analyzed.The paroxetine in dose of 20 mg/day and the citalopram in doses of 40 mg/day were superior to the placebo in pain relief, while fluoxetine in dose of 40 mg/day was not superior to the placebo.In a meta -analysis it was shown that the SSRIs are not superior to the ADT, although they have less EA.According to a published analysis, 30% of patients who receive SSRIs will present significant pain decrease, but also 30% will have EA.Currently, the use of ISRs is suggested in patients who do not respond to ADT, although the information that supports these recommendations comes from two small samples studies.The most frequent EA of the SSRIs are gastrointestinal disorders and sexual dysfunction.
Anticomicials
The mechanism of carbamacepine action is the locking of sodium and calcium channels dependent on voltage.This drug would beEffective for pain relief in patients with NDD, although studies in which the effectiveness of this agent was analyzed have important limitations.The most frequent EA of this drug are dizziness, blurred vision, nausea and vomiting.In addition, this drug is a powerful enzymatic inducer so it interacts with numerous drugs.
In a cross -sectional study, it was observed that phenytoin in a dose of 300 mg/day for two weeks was effective in reducing pain in patients with NDD, although in another test no superiority of the drug was demonstrated with respect to the placebo, and the individuals whoThey received the drug presented a higher EA rate.
Valproic acid in doses of 100 mg/day would be effective for the pain relief of the NPH, but its effectiveness in patients with NDD has not been demonstrated.
With oxcarbamacepine, drug with a mechanism of action similar to that of carbamacepine but with less pharmacological interactions, contradictory results have been obtained regarding their efficacy in patients with NDD.
Lamotrigine, sodium channel blocker dependent on voltage and glutamate release inhibitor in presynaptic terminals, was effective for pain relief in patients with NDD in doses of 25 to 400 mg/day after 6 weeks of treatment, although according to another publication, no benefits were observed with similar doses.In another study, this drug had an efficacy similar to amitriptyline in patients with NDD.The most frequent EA associated with the use of this drug are nausea, dizziness and skin rashes, which can be serious.Since it can be the cause of Stevens-Johnson syndrome, the drug suspension is recommended in the appearance of any form of exanthema.This EA is dose dependent and to limit its appearance it is recommended to start treatment with low doses.
Topiramate would exert its analgesic effect through various mechanisms.In one study it was observed that this drug in dose of 25 to 400 mg/day caused the relief of pain and sleep improvement in patients with NDD after 12 weeks of treatment;But in another standard, the difference with the placebo was not significant.The most frequent EA were fatigue, nausea, weight loss and drowsiness.
Zonisamide has been little studied and in an investigation it was not shown that its use reduced pain in patients with NDD.
Gabapentin and pregabaline, by means of the presynaptic block of calcium channels, inhibit the release of nociceptive neurotransmitters such as glutamate and substance P.
In two randomized and placebo -controlled studies, the efficacy of the gabapentin was evaluated in patients with NPH.In the first, with initial doses of 900 mg/day that increased up to a maximum of 3 600 mg/day, the gabapentin was higher than the placebo in terms of significant reduction in pain, sleep improvement, quality of lifeand of mood.In the other study, it was observed that 32% of patients received doses of 1,800 mg/day and 34% of those who received 2400 mg/day presented a pain relief greater than 50%.This drug would be as effective as nortriptyline, but with a better safety profile.
In patients with NDD, the gabapentin was superior to the placebo regarding pain reduction, the improvement of sleep, mood and quality of life disorders.In all studies it was observed that this drug is effective for analgesia when used in high doses, and that the doses of 900 mg/day are minimally effective.In a clinical trial it was observed that the effect of the gabapentin in dose of 1,800 mg/day was comparable to that of amitriptyline in dose of 75 mg/day, although the number of patients included was small.In another clinical trial with subjects with NDDHe verified that the combination of venlafaxin and gabapentin was superior to the latter as the only treatment.
In a recently carried out review, it was concluded that Gabapentín is effective for the treatment of NDD and NPH, although it would not be superior to carbamacepine.The pharmacokinetics of the gabapentin is not linear and its bioavailability orally is low, so dose adjustments are required for several weeks until it reaches the effective dose for pain treatment.The most frequent EA of Gabapentín are dizziness, drowsiness, headaches, diarrhea and nausea, which are generally mild to moderate.
The pregabaline in dose of 150 mg/day, 300 mg/day and 600 mg/day proved to be effective for the treatment of NPH in dual -blind randomized studies and placebo controlled, both in terms of pain reduction andImprovement of sleep, quality of life and mood.In tests of similar characteristics, it was also shown that this drug in dose of 300 mg/day and 600 mg/day is effective for pain relief in patients with NDD.It was also proven that the pregabalin is effective not only when used as monotherapy, but also when combined with other analgesic drugs.So far, no studies have been carried out that compare this drug with other drugs indicated for the treatment of neuropathic pain.The most frequent EA of the pregabalin are dizziness, drowsiness, peripheral edema and headaches.
Opioids
The effectiveness of these drugs for the treatment of neuropathic pain has not yet established.
The oxycodone of controlled release in doses of 20 to 60 mg/day is useful for the relief of pain by NPH, although this treatment has not observed improvement of sleep and mood.This dose drug of 20 to 80 mg/day has also proven to be effective for the treatment of NDD and an improvement of the quality of life in affected individuals has been observed.The authors emphasize that in all studies, this drug has been evaluated in combination with other analgesics.The most frequent EA are nausea, constipation, drowsiness, dizziness and sweating.
Tramadol acts on MU opioid receptors and also inhibits serotonin and noreprenaline reuptake.In patients with NPH and NDD it has been shown that this drug in dose of 100 to 400 mg/day is effective for the treatment of pain compared to placebo.The effectiveness of this drug would be similar to that of antidepressants and anti -initiation, although more studies should be carried out to verify this data.
In a study it was shown that morphine intravenously would be superior to the placebo for the treatment of neuropathic pain and allodynia.In another essay it was seen that morphine and metadona oral would be similar in terms of efficacy compared to adt amitriptyline and desipramine, although the incidence of EA with opioids was greater.The authors emphasize that opioids would be useful for the treatment of NPH and NDD, although some of its characteristics such as tolerance and the risk of addiction, as well as EA, limit their indication.
Topical treatments
In a study it was shown that 5% lidocaine patches are effective for the treatment of neuropathic pain and alodinia relief, and that cause few EA, mild and local.However, there is still not enough evidence to recommend this treatment as first choice therapy.
Capsaicin is effective for the treatment of NPH, but in patients with NDD the results were contradictory.The EA of this topical application drug are the sensation of burning and erythema.Its use is not recommended as a single treatment in patients with neuropathic pain.
NMDA antagonists
In patientsWith NDD it has been observed that dextrometorfano in high doses, between 380 and 400 mg/day, is effective for pain treatment, but no benefits have been demonstrated in patients with NPH.The most frequent EA are dizziness, sedation and ataxia.
Memantine is not effective for pain relief in patients with NDD and NPH.
Ketamine has a limited utility due to the EA that causes the CNS, which occur with slightly higher doses to those necessary to achieve analgesic effect.
Combination of pregabaline and gabapentin with opioids
It has been shown that the addition of a second analgesic, which could be an opioid, is useful when the gabapentin is insufficient for pain relief in patients with NPH and NDD.The combination of 60 mg/day of morphine with 2 400 mg/day of Gabapentín was more effective than any of the drugs evaluated individually, even in higher doses, for the decrease in pain in this population.In addition, with this combination the EA rate did not increase.
Discussion
From the studies analyzed, it follows that 50% of patients with NPH and 60% of those who have approximately NDD can achieve significant pain relief with drugs available today.Amitriptyline and gabapentin are the most studied drugs and those that have demonstrated greater efficacy.Although less studies with desipramine, imipramine, valproic acid, tramadol and oxycodone have been carried out, these drugs would also produce pain relief in 50% to 60% of patients.Likewise, pregabalin, venlafaxin, duloxetine and oxcarbamacepine would reduce this symptom by approximately 40% to 50% of patients.However, it should be noted that in most studies the results were analyzed after a few weeks of treatment, so the effectiveness of drugs with prolonged use is still unknown.
Many of the drugs available today (especially amitriptyline) have numerous contraindications and can produce potentially serious EA, which limits its use.Therefore, the authors highlight the need to elaborate new drugs for the treatment of neuropathic pain, such as lacosamide, which in a phase II study has been effective for pain relief in 43% of patients with this symptom of originneuropathicThey also indicate the importance of performing tests in which the efficacy of treatments combined with drugs with different mechanisms of action is evaluated, since with this strategy the doses would be reduced and a greater analgesic effect would be achieved.
In preclinical studies, it has been observed that the inhibition of sodium and calcium channels from the posterior spinal cord allowsynergistic
Combined treatments would be particularly useful in patients who do not obtain sufficient analgesia with a single drug and in those who do not tolerate high doses of a drug due to the appearance of EA.The authors also recommend the use of drug associations at the beginning of treatment, when pain is more intense
